Neuroradiologists disagree on switching to urokinase
Prior to its removal from the market three years ago, urokinase was the most widely used intra-arterial thrombolytic agent for stroke. Now it's again FDA-approved, but its fate is uncertain, as many neurointerventional radiologists have grown accustomed to using other drugs.
In the absence of urokinase, neurointerventionalists mainly turned to tissue plasminogen activator (tPA), followed by reteplase (marketed as Retavase), and abciximab, or ReoPro.
Although tPA carries significant bleeding complications, a low-dose methodology pioneered by Dr. David Hunter at the University of Minnesota Hospital has proved successful.
"Many felt that tPA would cause increased bleeding complications compared to urokinase, but that has not been our experience," said Dr. Gary R. Duckwiler, an associate professor of radiology and the director of the neuroradiology fellowship program at the University of California, Los Angeles. "By cutting down on the total dose, we have managed to cut down on bleeding complications."
Duckwiler does not intend to automatically switch back to urokinase without determining first if there are major benefits to doing so. Colleagues in Northern California, however, can't wait for their first shipment of reintroduced urokinase to arrive.
"We're thrilled to have urokinase back on the market," said Dr. Randall T. Higashida, chief of neurointerventional radiology at the University of California, San Francisco. "We're familiar with the dosages, best route for administration, and indications."
For the last three years, Higashida and colleagues have been trying to determine the optimal dosages of tPA and reteplase, particularly in conjunction with heparin and other anticoagulants. They just could not achieve the same comfort level they had with urokinase.
Initially approved by the FDA in 1978 for coronary artery thrombosis and catheter clearance, urokinase (marketed as Abbokinase) came under scrutiny in 1999 following an inspection of Abbott Laboratories in Chicago that revealed viral contamination. The active ingredient in urokinase is an enzyme produced by the human kidney and found in the urine.
To regain the FDA's blessing, Abbott upgraded its manufacturing facility, particularly by installing redundant testing for removing infectious agents, according to an Abbott spokesperson. Urokinase was reintroduced Oct. 10, approved for the lysis of acute massive pulmonary emboli.
Abbott's goal was a speedy reentry into the thrombolytic market, and focusing on the pulmonary embolism indication helped them toward that goal, the spokesperson said.
The FDA does not approve a product based on peer-reviewed literature. Rather, it looks at substantiating data from the manufacturer. Since this type of research requires hefty resources, manufacturers try to get their products approved in one area, knowing that they will be used for off-label purposes.
"Urokinase will be used for intra-arterial and intravenous thrombosis wherever it's found to be useful," said Dr. David Dixon, an interventional radiologist at St. Luke's Hospital in Kansas City, MO.
Duckwiler questions Abbott's commitment to acute stroke therapy. A phase III study of recombinant pro-urokinase in acute cerebral thromboembolism showed positive results. To be approved by the FDA, however, it requires a larger study, which is on hold.
Abbott said the price of urokinase will be comparable to what it was three years ago. Higashida remembers paying $250 for a 250,000-unit vial and generally using two to three vials per case. The cost of tPA is about $1500 for a 100-mg dose, he said, but that amount is for the intravenous dosage. Much smaller amounts are used intra-arterially.
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